How short peptides disassemble tau fibrils in Alzheimer’s disease

Ke Hou (), Peng Ge, Michael R. Sawaya, Liisa Lutter, Joshua L. Dolinsky, Yuan Yang, Yi Xiao Jiang, David R. Boyer, Xinyi Cheng, Justin Pi, Jeffrey Zhang, Jiahui Lu, Romany Abskharon, Shixin Yang, Zhiheng Yu, Juli Feigon and David S. Eisenberg ()
Additional contact information
Ke Hou: University of California, Los Angeles
Peng Ge: University of California, Los Angeles
Michael R. Sawaya: University of California, Los Angeles
Liisa Lutter: University of California, Los Angeles
Joshua L. Dolinsky: University of California, Los Angeles
Yuan Yang: University of California, Los Angeles
Yi Xiao Jiang: University of California, Los Angeles
David R. Boyer: University of California, Los Angeles
Xinyi Cheng: University of California, Los Angeles
Justin Pi: University of California, Los Angeles
Jeffrey Zhang: University of California, Los Angeles
Jiahui Lu: University of California, Los Angeles
Romany Abskharon: University of California, Los Angeles
Shixin Yang: Howard Hughes Medical Institute
Zhiheng Yu: Howard Hughes Medical Institute
Juli Feigon: University of California, Los Angeles
David S. Eisenberg: University of California, Los Angeles

Nature, 2025, vol. 644, issue 8078, 1020-1027

Abstract: Abstract Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer’s disease (AD)1. Previously, we found that in vitro, the d-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation2. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like (‘mock-amyloid’) fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.

Date: 2025
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DOI: 10.1038/s41586-025-09244-z

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